Production of substituted pyridines



United States Patent O PRODUCTION OF SUBSTITUTED PYRIDINES John E. Mahan, Bartlesville, Okla., assignor to Phillips Petroleum Company, a corporation of Delaware No Drawing. Application October 20, 1952 Serial No. 315,838

3 Claims. (Cl. 260-290) This invention relates to a process for the production of substituted pyridines. In one aspect this invention relates to a process for the production of alkyl substituted pyridines by the catalytic condensation of aldehydes and ketones with ammonia. In one specific embodiment this invention relation relates to a novel process for the production of 2-methyl-5-ethylpyridine.

Pyridine homologs are useful as intermediate compounds in the production of pyridine derivatives containing unsaturated side chains, such as the vinyl pyridines which are capable of undergoing copolymerization with other unsaturated organic compounds, such as butadiene, to produce potentially useful synthetic rubbers. Vinyl pyridines can be prepared from pyridine homologs, such as 2-methyl-5-ethylpyridine which is also known as aldehyde collidine and aldehydin, by various methods. For example, Z-methyl-S-ethylpyridine may be reacted with formaldehyde to produce the monomethylol derivative which, upon dehydration, produces 2 vinyl-S-ethylpyridine. Also, the ethyl group in Z-methyl-S-ethylpyridine may be dehydrogenated to produce 2-methyl-5- vinylpyridine.

' The condensation of aldehydes and ketones, either saturated or unsaturated, and derivatives thereof with am monia or its derivatives to form substituted pyridines is one of the oldest of organic reactions. See R. L. Frank et al., Journal of the American Chemical Society, 71, pages 2629 et seq. (August 1949), and R. L. Frank et al., Journal of the American Chemical Society, 68, pages 1368-9 (July 1946). The condensation reactions have been effected non-catalytically, and ammonium acetate and alumina have been employed in the prior art as catalysts for the reaction. Also, ammonium chloride has been reported as showing the same efiect as ammonium acetate. However, the prior art methods have a poor reputation for commercial production because of the formation of mixtures of pyridines and various by-products. In addition, when operating accordingto the prior art, relatively low yields of individual products have usually been reported.

This is a continuation-in-part of my application, S. N. 135,291, filed December 27, 1949 (now U. S. Patent 2,615,022), entitled Production of Substituted Pyridines.

It is an object of this invention to provide a novel process for the production of substituted pyridines.

'-It is another object of this invention to provide a process for the production of substituted pyridines that eliminates ditficulties in the prior art processes.

It is another object of this invention to condense aldehydes and ketones and their derivatives with ammonia in the presence of novel catalysts for the reaction.

It is another object of this invention to provide a novel process for the production of 2-methyl-5-ethylpyridine from low-boiling aldehydes and ammonia.

It is a further object of this invention to employ novel catalysts for the condensation of low-boiling aldehydes and ammonia to produce 2-methyl-S-ethylpyridine.

' Further and additional objects of my invention will be 1 pounds are suitable.

2,877,228 Patented Mar. 10, 1959 apparent from the disclosure and description hereinbelow.

I have found that substituted pyridines can be produced by the improved method of reacting an organic aldehyde or ketone or derivative thereof with ammonia in the presence of fluorine-containing catalysts.

According to my invention, ammonia and an organic aldehyde, ketone or derivative thereof that is known to condense with ammonia to form substituted pyridines are reacted in the presence of a fluorine-containing catalyst. Throughout this disclosure I will refer to the aldehydes, ketones and derivatives thereof as carbonyl compounds. The carbonyl compounds within the scope of my invention are known in the art, and illustrative examples of these compounds are set forth in detail in the abovenamed references. To produce 2-methyl-5-ethylpyridine I prefer to use an aldehyde containing no more than six carbon atoms per molecule, such as acetaldehyde, crotonaldehyde, and paraldehyde. However, my invention is not limited in scope to the production of this particular pyridine derivative nor tothe use of the specific aldehydes named above. For example, aldehydes and ketones, i. e. crotonaldehyde, benzalacetophenone, benzaldiacetophenone, ethylidene acetone, p-chlorobenzaldiacetophenone, anisaldiacetophenone, alpha acetylbutyrolactone, cyclopentano-ne, tetrahydropyrone and beta-cyclohexylpropionaldehyde, may be condensed with ammonia to form pyridine derivatives. In addition, mixtures of aldehydes and ketones, for example, benzaldehyde and acetophenone, benzaldiacetophenone and acetophenone, benzaldehyde and desoxybenzoin, benzalacetone and acetophenone, and benzalacetone and acetone, may be em ployed to form pyridine derivatives. Frequentlyand ad vantageously, the aldehydes can be employed as polymers, e. g., acetaldehyde can be employed .as paraldehyde. However, aliphatic aldehydes and ketones having a carbonyl group attached to a carbon atom with two hydrogen atoms attached thereto are preferred.

In accordance with the invention, I have found that salts of organic nitrogen-containing bases with hydrofluoric acid have excellent catalytic activity in the condensation of carbonyl compounds, such as aldehydes and ketones, with ammonia to produce pyridines and substituted pyridines.

Organic nitrogen-containing bases are applicable generally, in the form of their salts with hydrofluoric acids, as catalysts in said condensation reaction. In particular, salts of hydrogen fluoride with heterocyclic nitrogen com- These nitrogen compounds include heterocyclic nitrogen compounds and substituted derivatives thereof in which the ring structure is unsaturated, partially saturated and completely saturated. Examples include pyridines, quinolines, isoquinolines, piperi dines(hexahydropyridines), pyrroles, pyrrolidines, as well as substituted pyridines, piperidines, pyrroles, pyrrolidines, quinolines, isoquinolines, dihydro and tetrahydropyridines, partially hydrogenated quinolines and isoquinolines, and pyrroles (dihydropyrroles) particularly alkyl derivatives of the foregoing compounds. Examples of such compounds are pyridine, quinoline; 8-ethylquinoline; 4-hexy1- quinoline; isoquinoline; S-methylisoquinoline; methylpyridine; pyrrolidone; pyrrole; methylpyrrole; piperidine; 3-ethylpyrrolidine; 2,4-dimethylpyridine and the like. A preferred salt-forming organic nitrogen gase is methylethylpyridine which provides excellent yields of methylethylpyridine from the condensation of paraldehyde with ammonia.

The salts of hydrogen fluoride with amine compounds in general are suitable as catalysts in the process of this invention. One or more of the hydrogen atoms of the amine group can be substituted with organic radicals, such as alkyl, aryl, alkaryl, aralkyl, alicyclic or heterocyclic radicals, and thesev radicals, in turn, vcan have substituents longer than 2.0 hours.

3, of a non-interfering nature upon the radical. Such substituents, are, for example, cyano, nitro, hydroxyl, acyl, sulfonate, and other groups. The number of carbon atoms, in general, should not exceed 20, although a molecule with a greater number of carbon atoms can be utilized in some cases. Examples of suitable compounds of this class are salts of hydrogen fluoride with methylarnine, nitroethylamine, diethylamine, trimethylamine, ethylamine, bromoamines, phenylamine or aniline, N-alkylanilines, diethylaniline, benzoaniline, phenylglycine, diphenylamine, triphenylamine, alicyclic amines such as tetrahydro-beta-naphthylamine, diphenylguanidine, and the like. A preferred member of this group is the hydrofluoric acid salt of guanidine.

Also comprehended within the scope of the catalytic materials of this invention are the salts of substituted ammonium hydroxides with hydrofluoric acid. Preferred members of this group are tetra-alkylammonium hydroxide in which each alkyl group contains from 1 to 6 carbon atoms, and trimethyl benzyl ammonium hydroxide (Triton B). One or more of the alkyl groups can be replaced by a hydrogen atom, aryl, aralkyl, alkaryl, 'heterocyclic, or alicyclic radical which can be substituted with non-interfering groups, as previously identified in connection with the discussion of amine compounds. Ex amples of such compounds are the salts of hydrogen fluoride with quaternary ammonium hydroxides, such as tetramethylammonium hydroxide, phenylmethyldiethylammonium hydroxide, phenyltrimethylammonium hydroxide, benzyltrimethylammonium hydroxide, cyclohexyltrimethylarnmonium hydroxide, pyridyltriamylam- 'monium hydroxide and the like.

I have found it preferable to employ the catalysts in relatively small amounts. Usually from 0.2 to 10.0, preferably 1.5 to 5.0, Weight percent of catalyst based on the carbonyl compound is employed.

M01 ratios of ammonia to carbonyl compound undergoing condensation within the range of 1:1 to 12:1 are utilized, but higher ratios are operable in my process. I prefer to use mol ratios of ammonia to carbonyl compound within the range of 2:1 to 9:1 in order to maintain the volume of material to be handled at a low level.

The ammonia for the reaction is usually in an aqueous solution, but in some instances it may be desirable to conduct the reaction with anhydrous liquid ammonia. When an aqueous ammonia solution is utilized for the reaction, ammonia and water are supplied to the reaction in a ratio such that a solution containing 10 to 90 weight percent ammonia is formed.

Optimum reaction temperatures are within the range of 300 to 650 F., preferably 450 to 550 F. The reaction is usually effected in the liquid phase, and, consequently,

a closed pressure reactor, the autogenous pressures developed by the reaction mixture at the reaction temperature are satisfactory. These pressures are usually within the range of 850 to 2500 pounds per square inch gauge. The reaction period, or the time during which the reaction mixture is maintained at the desired reaction temperature, may vary from 5.0 minutes to 5.0 hours, preferably no However, the data hereinbelow show that good yields of substituted pyridines can be obtained by cooling the reaction mixture, such as by quenching in ice water, as soon as the desired reaction temperature is attained. I have also found'it desirable to cool the reaction mixture rapidly, such as by quenching in ice water, after the desired reaction period has expired. In this manner improved yields are obtained over procedures wherein the reaction mixture is allowed to cool slowly after expiration of the reaction period. Reaction periods longer than 2.0 hours may be used, but they are not essential to the process. Little, if any, advantage is gained by so operating, and, actually, the longer reaction periods may be conducive toward decomposition of the 4 reaction products, resulting in decreased yields of the desired substituted pyridinesm At the end of the desired reaction period, the temperature is lowered to about room temperature, and the substituted pyridines are recovered from the reaction mixture by any suitable method, such as fractional distillation.

In some instances it may be found desirable to employ an emulsifying agent in the reaction mixture. It is preferred that any emulsifying agent so employed be soluble in at leastone of the components of the reaction mixture. Emulsifying agents that may be used include salts of saturated or unsaturated fatty acids containing at least six and not more than 18 carbon atoms, sulfates, such as-lauryl sulfate, and sulfonates, such as alkaryl sulfonates. Non-ionic detergents, such as ethylene oxide condensation products of organic acids, alcohols, mercaptans, phenols, amides, and the like, as Well as cationic surface active agents of the quaternary ammonium ion type may also be used. The emulsifying agent is usually added in the proportions of 0.1 to 5.0 percent by weight based on the carbonyl compound.

Although I have described my invention as a batch process, the invention may also be practiced in a continuous operation, and such operation is within the scope of my invention. In one embodiment of a continuous process, reactants are introduced continuously to a suitable pressure reactor from which a portion of the reaction mixture is withdrawn continuously. Reaction products are separated therefrom, and unchanged reactants are then recycled to the reactor.

In another aspect of the invention, phosphate glasses are utilized as synergists for the condensation reactions catalyzed by the novel fluorine-containing catalyst hereinbefore set forth. Calcium phosphate glasses can be used, but I usually employ water soluble alkali metal phosphate glasses, and I prefer to use a water soluble sodium phosphate glass. Descriptions of these glasses and the methods of producing them are contained in the articles by Partridge, Chemical and Engineering News 27, 214-217 (1949) and by Schwartz et 211., Industrial and Engineering Chemistry 34, 32-40 (1942). The metal phosphate glasses, and particularly the sodium phosphate glasses, are readily prepared by heating the corresponding metal metaphosphate to a temperature above its melting point and rapidly cooling the resulting liquid to form a vitreous or glassy product. The glasses contain P 0 and metallic oxides in varying amounts, and the ratio of P 0 and metallic oxides extends over a wide range. More specifically, the glasses I employ can contain a minor, say 0.1 mol percent, amount of metallic oxide, and the concentration of the metallic oxide may vary up to 60 mol percent. The preferred glass is available commercially, and it is known as sodium hexametaphosphate. This preferred glass contains approximately equimolar proportions of Na O and P 0 The water soluble metal phosphate glasses are introduced to the reaction mixture either in the form of a solid or in an aqueous solution, and, when I refer to phosphate glasses in my specification and claims, it will be understood that I am referring to phosphate glasses in the form of a solid or an aqueous solution. Since water is formed during the condensation reaction, it is sometimes desirable to introduce the glasses in solid form in order to limit the amount of water present in the reaction mixture. In operations where it is necessary to employ a large amount of the glasses in the reaction it may be desirable to introduce the glasses in an aqueous solution to facilitate the handling and transporting of the glasses. Usually, from 0.05 to 10, preferably, 0.1 to 6 weight percent of the glasses based on the carbonyl compound is employed. The total amount of fluorine-containing catalyst and metal phosphate glass synergist is usually not above 10 weight percent based on the carbonyl compound.

The examples hereinbelow are illustrative of my invention. In these experiments a stainless steel bomb of 1400 milliliter capacity was employed. The bomb was provided with a thermometer well together with an inlet line containing a valve, and the bomb was wrapped with resistance wire and thus heated electrically. In conducting the experiments the bomb was charged with reactants, such as paraldehyde, aqueous or liquid ammonia and catalyst (when used) and firmly sealed. Air was removed from the bomb by adding nitrogen to a pressure of one hundred pounds per square inch and venting until the pressure was again atmospheric. A period of one hour to one and one-half hours was required for the bomb to attain the desired reaction temperature, and the duration of the run was the interval of time that the bomb was held at the desired reaction temperature. Agitation of the bomb was provided by an electrically driven platform rocker. At the end of the reaction period the reaction mixture, after venting excess ammonia, was extracted with benzene, and the extract was fractionated to recover the pyridine derivatives.

Example A series of runs Was made to demonstrate the superior yields obtained when using the catalytic materials of my invention. One run was made non-catalytically to serve as a control. All runs were made under substantially identical conditions of temperature, pressure mol ratios of reactants, and the like, as follows:

Temperature F 490-500 Reaction time hours 3 Ammonia/paraldehyde, mol ratio 7.91 Charge:

Paraldehyde ....grams 170 Water An 21 l Ammonia do 173 The following results were obtained Yields, M01 Percent Male 0! Catalyst Catalyst z-Methyl- Used Plcolines fi'ethylpyridine a-Meth l-fi-eth 1 idlne-HF Salt. 2.8 75. 2 1s Guannime-H s izii 1.2 73.6 .18 Triton B-HF Salt 2. 8 72. 0 .03 one 2.6 56.3

"lrimethyl benzyl ammonium hydroxide.

While the invention has been described in connection with present, preferred embodiments thereof, it is to be understood that this description is illustrative only and is not intended to limit the invention.

I claim:

1. In the process for producing pyridine derivatives by the interaction of a carbonyl compound selected from the group consisting of low-boiling aldehydes and ketones with ammonia, the improvement comprising efiecting the reaction in the presence of a salt of an organic nitrogencontaining base with hydrogen fluoride and in the presence of a water soluble metal phosphate glass as a synergist for the catalytic salt.

2. In a process for producing pyridine derivatives by the interaction of a carbonyl compound of 3 to 6 carbon 'atoms selected from the group consisting of aldehydes and ketones with ammonia, the improvement comprising effecting the reaction in the presence of a catalyst comprising a salt of hydrogen fluoride with a compound selected from the group consisting of 2-methyl-5-ethylpyridine, guanidine, and trimethylbenzylammonium hydroxide and in the presence of a water soluble metal phosphate glass as a synergist for the catalytic salt.

3. The process for preparing Z-methyl-S-ethylpyridine which comprises reacting a carbonylcompound of 3-6 carbon atoms selected from the group consisting of aliphatic aldehydes and aliphatic ketones wherein the carbonyl group is attached to a carbon atom having two hydrogens attached thereto with 1-12 mols of ammonia per mole of carbonyl compound at a temperature in the range of 300-600 F. and at a pressure in the range of 850 to 2500 pounds per square inch gauge in the presence of a catalystcomprising a salt of hydrogen fluoride with a compound selected from the group consisting of 2- methyl-5-ethylpyridine, guanidine, and trimethylbenzylammonium hydroxide and in the presence of sodium phosphate glass as a synergist for the catalytic salt.

References Cited in the file of this patent UNITED STATES PATENTS 2,184,235 Groll et al. Dec. 19, 1939 2,413,598 Ballard et al. Dec. 31, 1946 2,520,097 Hearne et al Aug. 22, 1950 2,615,022 Mahan Oct. 21, 1952 UNITED STATES PATEN'? OFFICE CERTIFICATE OF CORRECTION Patent No* 2,877,228 March 10, 1959' John E, Mahan It is hereby certified that error appears in the printed specification of the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 1, line 20, strike out the Word"'relation"; column 2 line 63',

for "game" read bass column 5, line 42, for "3Me'thyl-" read 2-Methyl- Signed and sealed this 25th day of August 1959,

(SEAL) Attest:

KARL Ht AXLINE.

ROBERT C. WATSON Attesting Officer Commissioner of Patents 

1. IN THE PROCESS FOR PRODUCING PYRIDINE DERIVATIVE BY THE INTERACTION OF A CARBONYL COMPOUND SELECTED FROM THE GROUP CONSISTING OF LOW-BOILING ALDEHYDES AND KETONES WITH AMMONIA, THE IMPROVEMENT COMPRISING EFFECTING THE REACTION IN THE PRESENCE OF A SALT OF AN ORGANIC NITROGENCONTAINING BASE WITH HYDROGEN FLUORIDE AND IN THE PRESENCE OF A WATER SOLUBLE METAL PHOSPHATE GLASS AS A SYNERGIST FOR THE CATALYTIC SALT. 